Asthma is an inflammatory disease caused by the deregulated development and activation of CD4+ T helper type 2 (Th2) cells that secrete IL-4, IL-5, and IL-13. This phenotype is initiated by common environmental factors and has been correlated with lower respiratory tract infections in children, including influenza, respiratory syncytial virus and rhinovirus infections. Th2-secreted cytokines are able to promote the migration and activation of other cell types, leading to inflammation in the lungs. IL-5 and IL-13 induce granulocyte activation and induce mucus production from goblet cells. We have demonstrated that primary human CD4+ nave T cells polarized in vitro under Th2 conditions are sensitive to treatment with Type I Interferon (IFN-?/?), resulting in decreased levels of secreted Th2 cytokines and GATA3 expression. As the development of Th2 cells is important during the onset of asthma, understanding the effects of this cytokine on memory Th2 cells will be important in understanding how to control reoccurring asthmatic exacerbations without the use of steroids. Additionally, determining the acute regulatory mechanisms on memory Th2 cells by IFN-?/? will be important to understanding how IFN-?/? is applicable for the treatment of severe asthma, which will be addressed in Aim 1. Additionally, the regulatory effects of IFN-?/? in asthmatics have yet to be determined. Thus, Aim 2 will determine the similarities and differences in Th2 regulation by IFN-?/? in asthmatic individuals compared to the non-asthmatic cohort. Based on our preliminary data, we hypothesize that IFN-?/? plays a critical role in the regulation of memory Th2 cells and that a defect exists in signaling and/or response to this cytokine in asthmatic patients. We therefore propose to determine the effects of IFN-?/? on primary asthmatic Th2 cells. If asthmatic Th2 cells are sensitive to IFN-?/?, this cytokine could be a potential treatment for severe asthma and other chronic allergies. This hypothesis will be tested using the following aims to guide our research: 1. Determine the molecular mechanism by which IFN-?/? inhibits TCR-mediated Th2 cytokine expression in memory CD4+ T cells. 2. Determine the role of IFN-?/? in reversing Th2 commitment in cells isolated from allergic asthma patients. Determining how IFN-?/? modulates Th2 development and activity is key to understanding the novel pathway is associated with atopic disease. It is through this proposal we hope to use the gained information to assess IFN-?/? as an effective tool to control Th2 hypersensitivity.